Our overall goal is to provide a better understanding of the neuronal basis of human memory in health and disease. Despite considerable research, there is a critical dearth of data at the single neuron level in humans on brain mechanisms underlying declarative memory. Such data can bridge the gap between basic neuronal research in animals, and human functional magnetic resonance imaging (fMRI) research. Direct recording from depth electrodes implanted in human medial temporal lobe (MIL) areas is possible because our subjects are epilepsy patients who require electrode placement to identify the seizure focus for later resection. Our NIH-funded studies to date have elucidated key characteristics of single neuron responses to complex visual stimuli during encoding and retrieval. Now our primary objective is to characterize single neuronal responses and local field potentials (LFPs) during all three major aspects of human declarative memory processes: (1) associative representations, (2) temporal sequential organization of events, and (3) abstraction of common features among related memories. We propose to use tasks that more closely approximate human episodic memory, including sequences of stimuli and stimulus associations and an immersive virtual reality navigational task. The central hypothesis of this study is that neurons in the medial temporal lobe use two codes for declarative memory: (1) a rate code, based on neuronal firing rate, which is sparse, accentuated by inhibition, highly specific to complex stimuli, yet strikingly abstract. It is this code that underlies associative representations and abstraction of common features. And (2) a temporal code, based on timing of spikes that is driven by oscillatory patterns and phase locking of neuronal firing. It is this code that underlies temporal sequential organization of events. We remain the main group in a position to address these fundamental questions about human memory at both the single neuron level and the level of local field potentials. Our studies pave the way to understanding and managing memory impairment in Alzheimer's, temporal lobe epilepsy and other neurological diseases.